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Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson's disease model.

ABSTRACT: Supporting data for "Disruption of lysosomal proteolysis in astrocytes facilitates midbrain proteostasis failure in an early-onset PD model", DOI: T.B.D. Related to Figure 4A and S4A-B. KN43-66 - TMTpro | 4plex | Whole cell proteome - MS3 KN67-72 - TMTpro | 4plex | Enriched Phospho-peptides - MS2 KN73-96 - TMT | 9plex | Whole cell proteome - MS2

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Alban Ordureau

PROVIDER: MSV000090202 | MassIVE | Wed Aug 24 14:45:00 BST 2022

REPOSITORIES: MassIVE

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Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson's disease model.

Morrone Parfitt Gustavo G Coccia Elena E Goldman Camille C Whitney Kristen K Reyes Ricardo R Sarrafha Lily L Nam Ki Hong KH Sohail Soha S Jones Drew R DR Crary John F JF Ordureau Alban A Blanchard Joel J Ahfeldt Tim T

Nature communications 20240110 1

Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson's Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphoryl ...[more]

PMID: 38200091

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Metabolic alterations in Parkinson's disease astrocytes.

Project description:In Parkinson`s disease (PD), the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta is associated with Lewy bodies arising from the accumulation of alpha-synuclein protein which leads ultimately to movement impairment. While PD has been considered a disease of the DA neurons, a glial contribution, in particular that of astrocytes, in PD pathogenesis is starting to be uncovered. Here, we report findings from astrocytes derived from induced pluripotent stem cells of LRRK2 G2019S mutant patients, with one patient also carrying a GBA N370S mutation, as well as healthy individuals. The PD patient astrocytes manifest the hallmarks of the disease pathology including increased expression of alpha-synuclein. This has detrimental consequences, resulting in altered metabolism, disturbed Ca2+ homeostasis and increased release of cytokines upon inflammatory stimulation. Furthermore, PD astroglial cells manifest increased levels of polyamines and polyamine precursors while lysophosphatidylethanolamine levels are decreased, both of these changes have been reported also in PD brain. Collectively, these data reveal an important role for astrocytes in PD pathology and highlight the potential of iPSC-derived cells in disease modeling and drug discovery.

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